Abnormal immune mechanisms are being studied in patients with HB Ag negative chronic active hepatitis and primary biliary cirrhosis selected according to strict diagnostic criteria. A detailed immunologic evaluation is undertaken, which includes the following techniques: multiple intradermal antigen tests, primary immunization with both protein and polysaccharide antigens, quantitation of T and B cell populations using Rosette tests and immunofluorescence, HLA typing, measurement of serum immunoglobulins and functional assay of serum complement components. The in vitro cytotoxic capacity of lymphocytes and lymphocyte subpopulations (T, K and B cells) against several liver-specific and non-hepatic target cells in tissue culture is being evaluated. In addition, the capacity of the reticuloendothelial system to clear nonspecific and immunospecific particles from the circulation is being assessed. Nonspecific clearance is determined from the rate of clearance of 125I-microaggregated albumin and immunospecific clearance from the fate of 51Cr-labeled autologous red cells coated with a specific IgG or IgM antibody. The results of these studies include the demonstration of defects in spontaneous cell-mediated cytotoxicity and immunospecific reticuloendothelial clearance in primary biliary cirrhosis.